Sodium channels are integral membrane proteins that form ion channels in the plasma membrane of excitable cells. They are classified as voltage-gated sodium (NaV) channels, which permit the influx of Na+ ions that mediate action potentials in excitable cells; and ligand-gated sodium channels, which bind a ligand that triggers the influx of ions leading to similar action potentials.
NaV channels, like calcium and potassium channels, are composed of a very large and complex α-subunit on the surface of the cell which includes four domains (DI-DIV), each with six transmembrane α-helix segments (S1-S6) and including a pore that allows the influx of Na+ ions into the cell (FIG. 1; see also Clare 2010 Expert Opin. Investig. Drugs 19(1):45-62). For NaV channels, a single gene encodes all of these domains. Transmembrane segment 4 (S4) within each domain of NaV channels contains positively charged amino acids (FIG. 1) that act as a voltage sensor. The intracellular loop that connects Domains III and IV contains sequences that are reportedly involved in inactivation. NaV channels interact with other proteins on the cell surface termed β-subunits, which are involved in channel kinetics and voltage-dependent gating functions. NaV channels reportedly exhibit diverse functional properties and distinct expression patterns, which imply specialized functions among the channels and predisposes some for roles in transmitting specific signals, for example, pain signals.
In spite of many efforts to elucidate the properties and functions of human NaV channels, the large size and complex nature of their structure makes it difficult to study the global aspects of their biological activity and their involvement in the pain response. This difficulty is increased by the fact that global deletion is lethal; Scn9A−/− pups die shortly after birth, apparently due to a failure to feed. Therefore, there is a need in the art for compositions and methods that do not rely on in vitro systems (for example, in vitro-transfected cells containing constructs expressing human NaV channels in culture) but that instead employ more biologically sensible approaches to making non-human animals and cells that include whole human NaV channels or chimeric NaV channels containing specific human fragments associated with NaV channel activation and that can function in facilitating the pain response.